Mitochondria are intracellular organelles responsible for energy metabolism. Consequently, mitochondrial dysfunction is damaging, particularly to neural and muscle tissues which have high energy demands.
Mitochondrial dysfunction is central to a number of human degenerative diseases, and can be due to primary defects in genes encoded by mitochondrial DNA, by mutations in nuclear encoded genes, or due to secondary consequences of other defects. Oxidative damage to the mitochondrion is a major factor in the pathophysiology of these diseases, because the mitochondrial respiratory chain is the major source of reactive oxygen species (ROS) within most human cells. These diseases include Parkinson's disease, Friedreich's Ataxia, Wilson's Disease, mtDNA diseases, diabetes, motor neuron disease and the non-specific loss of vigor associated with aging. Oxidative damage to mitochondria also contributes to the pathophysiology of inflammation and ischaemic-reperfusion injury in stroke, heart attack and during organ transplantation and surgery. Methods for treatment of diseases related to mitochondrial dysfunction are described in U.S. Pat. Nos. 6,956,028 and 6,511,966.
Mitochondrial anti-oxidant compounds are known and have been used as treatments, nutritional supplements and medium components. U.S. Pat. Nos. 6,984,636, 5,607,980, 5,472,698, 5,292,538, 5,536,645, 5,326,699, 6,562,869 and 6,479,069.
The predominant form of coenzyme Q in humans is coenzyme Q10 (CoQ10), which contains 10 isoprenoid units in the tail of the p-benzoquinone nucleus, whereas the predominant form in rodents is coenzyme Q9 (CoQ9). CoQ10 is the precursor of CoQ9, so administration of CoQ10 to rats would provide CoQ9 when systemically required. Coenzyme Q10 (also known as ubiquinone) is present in all tissues and membranes in highly variable amounts. Various functions are attributed to coenzyme Q, depending on distribution and concentrations. It is a redox component; by interaction with NADH it is converted into the reduced form: coenzyme-QH2 (e.g. ubiquinol), which plays the electron-carrier role in the mitochondrial electron transport chain. This electron carrier role was considered for a long time to be its only function. However, its broad distribution provides a clue to its additional cellular role,—claimed to be the only endogenously synthesized lipid soluble antioxidant (Ernster, L and Dallner, G, Biochemical, physiological and medical aspects of ubiquinone function. Biochem. Biophys. Acta, 1271:195-204, 1995). Coenzyme-QH2 is a highly efficient antioxidant in preventing lipid, protein and DNA-oxidative damage. Coenzyme QH2 is continuously regenerated from coenzyme Q10 by intracellular reduction systems. In liposomes and in a mixture of lipoproteins, it was shown that CoQ10 is preferentially utilized as an antioxidant when both this lipid and α-tocopherol were available. In some pathologic processes, when tissue concentration of CoQ10 is decreased, it may be advantageous to supplement CoQ10 by dietary supplement (Turunen M, Appelkvist E L, Sindelar P and Dallner G, Blood concentration of coenzyme Q10 increases in rats when esterified forms are administered. J. Nutr., 129:2113-2118, 1999). However, the effect of exogenous source of administration of CoQ10 is difficult to interpret because in the absence of coenzyme-QH2 (CoQH2), the former can also be a pro-oxidant while acting as an electron acceptor that facilitates respiration.
From the mid-1970s, since CoQ10 was synthetically prepared, it was used as a therapeutic agent in human physiological deficiencies, since CoQ10 is an integral component of the electron transport chain in mitochondria of humans. U.S. Pat. Nos. 6,417,233, 6,867,024, and U.S. Patent Application Publication No. 2006/0024247. In the electron transport chain, CoQ10 receives electrons from NADH, forms reduced CoQ10 (CoQH2) and passes the electron to cytochrome c, required for energy synthesis. After transfer of the electrons, reduced CoQH2 is again oxidized to the quinone form (CoQ10).
During physiological disorder, e.g. oxidative stress, the oxidation-reduction cycle of CoQH2□CoQ10 is impaired and CoQ10 is randomly degraded to form polar aberrant metabolites. Oxidation of both CoQH2 and CoQ10 by systemic oxygen-centered free radicals produces intractable agglomerates. Oral intake or topical application of CoQ10 alone, in such circumstances, is not able to completely restore the metabolic balance.
Accordingly, there is a need for compounds, compositions and methods that limit or prevent damage to organelles, cells and tissues initiated by mitochondrial dysfunction. The present invention fulfills the aforementioned needs and provides other related advantages.